At Queen’s University Belfast, physiology education and research has built a legacy of discovery science with translation in health and disease. Application of physiology research approaches to cancer research has identified novel targets with the potential to enhance therapy and improve outcomes. This presentation will highlight two of our research programmes: ‘radiotherapy-induced bladder dysfunction’ and ‘ion channels and cancer’. 

Radiotherapy aims to maximise tumour control and minimise adverse effects on neighbouring normal tissue.  Despite innovations that more precisely deliver radiation to tumours, many patients experience side-effects from normal tissue toxicity.  In pelvic cancers, radiotherapy can evoke acute radiation cystitis and bladder dysfunction which often resolves over time. Late effects are less common, occurring months to years post-radiotherapy, but cause significant and irreversible bladder dysfunction. Investigation of bladder physiology after irradiation is uncovering the underlying pathophysiological mechanisms.  CT image-guided radiation of mice bladders recapitulated the clinical context where around 50% of mice exhibited altered voiding patterns with frequent, small volume voids.  Interestingly, contractility of bladder tissue strips was changed after irradiation, whether or not voiding patterns were changed. Neurogenic-contractions were smaller in the acute phase, 2 weeks post-radiation and while they increased over subsequent months, did not fully resolve. Impaired contractility was not explained by aberrant voltage-gated Ca²⁺-activity as depolarization-mediated contractions were unaffected by irradiation. Muscarinic-contractions were also unaffected; therefore, pre-synaptic mechanisms may be radiation-sensitive and further work is needed to better understand this (1).

Ion channels are linked with many cancer hallmarks, with altered mRNA and protein expression of diverse ion channels across many cancers vs. normal tissue commonly reported (2).  Interestingly, further changes are detected following cancer treatment. Specialist physiology techniques are necessary to reveal whether these changes translate to aberrant ion channel signalling which contributes to cancer growth, treatment resistance and metastasis. Such work can indicate whether ion channel drugs, used in the clinical management of other conditions, could have therapeutic benefit for cancer.

We, and others, have shown that upregulation of the L-type Ca²⁺-channel, Ca_V1.3, encoded by CACNA1D, is common in prostate cancer, tracking with Gleason grade and metastasis status. Hormone therapy conditions, via androgen deprivation or androgen receptor inhibition, further upregulates CACNA1D expression, sustains Ca_V1.3 overexpression and may enhance localisation at the plasma membrane.  Of note, Ca_V1.3 ion channel activity could only be detected during hormone therapy conditions with patch-clamp electrophysiology or Ca²⁺-imaging (3). This suggests that Ca_V1.3 activity, emerging during hormone therapy, when proliferative capacity is reduced may facilitate adaptation and survival of treatment-resistant cells that eventually drive recurrence. It remains to be seen whether repurposing calcium channel blockers could be of therapeutic benefit during hormone therapy.

The presentation will share how using physiology lenses in cancer research can foster collaborative, interdisciplinary working that may ultimately improve patient outcomes and quality of life.